The human body and in particular its regulation system continuously regulates the whole metabolism with respect to internal demands (oxygen, nutrition etc.) or external physical conditions and changes (temperature, humidity, etc.) or physical or intellectual efforts (physical working, sport, movements, intellectual work etc.) and all kind of threats (bacterial, viral etc.) including pathological disorders. Many of these regulation mechanisms act in a characteristic way on blood flow and/or the microcirculation and/or its regulation mechanisms. Therefore, the microcirculation and more precisely the associated hemodynamic response can be considered as an indirect indicator of body regulation actions. Stimuli, external or internal induce changes in the microcirculation or more precisely changes in the hemodynamic response. The same is in general also valid for all living beings, animals or even plants (where instead of hemodynamic response the plant perfusion can be monitored). Therefore, many regulation mechanisms in living beings can be partly monitored via the indirect response of the hemodynamic system or via changes in blood concentration and/or perfusion. As the regulation system reacts to external stimuli, an associated hemodynamic response can be used as an indicator for normal or abnormal response of the regulation system. Similar functional aspects are widely known in functional magnetic resonance imaging (fMRI).
Functional Optical Coherent Imaging (fOCI) is based on a non-contact imaging modality utilizing, to a large extent, the physical properties and in particular the coherence properties of light. This imaging modality integrates new and ultrafast detector technology, combined with an appropriate coherent light source and an image processing unit for extracting the flow characteristics of the observed body area of interest. Thereby, it allows for the diagnosis, or observation of multiple diseases and disorders such as peripheral vascular diseases, skin irritations, diabetes, burns, organ transplants, tissue grafts and even functional brain imaging. This method is in particular non-invasive because it involves no physical contact; therefore risk of infection and discomfort are greatly avoided.
As a sub-class of these optical coherent imaging methods, but not limited to them, there exists Laser Doppler Imaging (LDI), Laser Doppler Spectroscopic Imaging (LDSI), Laser Speckle Imaging (LSI), and Optical Coherence Tomography (OCT) which will all be described hereafter.
Laser Doppler Imaging (LDI) is a coherent imaging technique that allows the imaging of moving particles, e.g. blood flow or red blood cells, with good discrimination between perfusion, flow velocities and the concentration of the moving particles. It has made great progress during the last two decades from the initial proposals based on a scanning instrument towards a state of the art biomedical instrument, mainly due to a parallel imaging instrument based on a fast CMOS array of photo detectors.
The underlying concept is based on the fact that the back-reflected light from a biological sample or tissue or organ illuminated with a coherent light source consists of the superposition of two components: the first from the non-moving, static particles (e.g. the tissue) and the second from the moving, dynamic particles (e.g. the cells in the blood). The intensity fluctuations of this superposition encode the aforementioned flow information which can be extracted by sampling the fluctuations at a sufficiently high frequency and by applying appropriate signal analysis.
Current state of the art Laser Doppler Imaging techniques are disclosed in the three following patents and patent application, respectively, as well as in the publications “Serov A., Lasser T., High-speed laser Doppler perfusion imaging using an integrating CMOS image sensor, Optics Express 13#17: 6416-6428, August 2005” and “Serov A., Steinacher B., Lasser T., Full-field laser Doppler perfusion imaging and monitoring with an intelligent CMOS camera, Optics Express 13#10: 3681-3689, May 2005”.
In U.S. Pat. No. 6,263,227 there is described an apparatus for imaging micro vascular blood flow. The concept of using a 1D or 2D matrix of conventional photo detectors is described. The imager can work in two modes—scanning or static. In the scanning mode, a laser line is projected on the area of interest. The signals from the illuminated areas are detected by a 1D matrix of photo detectors. By scanning the illuminating laser light over the area of interest, a 2D perfusion map is obtained. In the static mode the whole area of interest is illuminated by an expanded laser beam or by light exiting an optical fiber. The Doppler signal is measured by a 2D matrix of photo detectors. Each photo detector has its own electronics for signal processing. A CCD camera is used to observe the object of interest. The perfusion maps are superimposed on the photographic image obtained with the CCD.
Laser Doppler perfusion imaging with a plurality of beams is known from the patent application WO03063677. Here, a structured illumination is used for illuminating a plurality of points or an area of interest. The Doppler signal from the illuminated areas is detected with a non-integrating random access high pixel readout rate image sensor. This single CMOS image sensor is used for detecting the Doppler signal and to obtain a photographic image of the object of interest.
The publication document WO06111836 describes an instrument and method for high-speed perfusion imaging. In contrast to both previously cited patents, the instrument described here uses integrating detectors which allow the signal to noise ratio to be improved compared to measurements with non-integrating detectors. Further, full field homogeneous illumination increases both resolution and read-out speed and makes it possible to combine LDI with speckle imaging, thus extracting more information.
Laser Doppler Spectroscopic Imaging (LDSI) is extending Laser Doppler Imaging (LDI) by making use of multi-wavelength illumination of the sample for gaining concentration information of specific molecules and compounds. The underlying LDI method makes it possible to achieve good discrimination between the concentration of the flowing molecules or compounds in the blood and the non-flowing molecules and compounds of the tissue. A prominent example of this method is the imaging of the oxy-deoxy-hemoglobin ratio which is possible with a two-wavelength illumination at 800 nm (e.g. the isobestic point) and 700 nm (providing an order of magnitude difference in absorption between the oxy- and the deoxy-state).
Laser Speckle Contrast Imaging (LSI) is as LDI a full-field flow imaging technique. The advantage of this approach is a fast image acquisition which is achieved at the expense of spatial and temporal resolution. This technique is exploited for flow measurements; however the acquired signal does not permit a discrimination between concentration and speed of the moving particles. Both said parameters influence the system response in the same manner; therefore the information content is different when compared with LDI. In addition, the system response is not linear with velocity since a finite camera integration time influences the measurement. A review of LSI can be found in the publication “Briers J. D., Laser Doppler, speckle and related techniques for blood perfusion mapping and imaging, Physiol. Meas. 22, R35-R66, 2001”.
The LSI system obtains flow-related information by measuring the contrast of the image speckles formed by the detected laser light. If the sample consists of, or contains moving particles, e.g. blood cells, the speckle pattern fluctuates. The measured contrast is related to the flow parameters (such as speed and concentration of moving particles) of the investigated object. The contrast value is estimated for a certain integration time (exposure time) of the sensor. The faster the speckle pattern fluctuations, the lower the contrast value measured at a given exposure time. The control unit defines the exposure time of the image sensor to determine the range of the measured flow-related data related to the image contrast in LSI mode. Here, the integration time defines the range of measured speeds. The use of integrating image detectors is mandatory. Until now only the use of CCD type image sensors was reported for the technique.
Optical Coherence Tomography (OCT) represents an additional imaging modality (see for example “Saleh B. E. A., Teich M. C., Fundamentals of Photonics, Wiley & Sons Inc, New York, 2nd Edition 2006, ISBN 978-0-471-35832-9”), from which flow data and in particular blood flow can be extracted from the acquired tomograms. A particular technique represents resonant Doppler flow imaging based on an interferometric imaging concept, where blood flow data is acquired via a path length modulation in the reference arm. This technique is disclosed for example in the documents WO2007085992; WO2006100544; EP1872084.
The hemodynamic mechanisms, which are well known in various medical fields and in particular in functional magnetic resonance imaging (fMRI), occur at timescales of from ˜10 ms to several seconds or in a frequency range of 0.01-100 Hz. Over this timescale or frequency range, several natural body functions are overlaid masking the small changes of the hemodynamic system in response to the stimuli. The most important hemodynamic signals are the cardiac cycle, the natural heart beating driving the blood circulation. In addition, breathing as well as numerous other periodic components such as vasomotion are present and contribute strongly to the total signal observed. Overall, these natural functions are often stronger than the induced hemodynamic changes in response to the stimuli. In all mentioned optical coherent imaging modalities, but not limited thereto, these small changes are often not seen in the direct perfusion, speed or concentration maps. Even if seen, they are mostly not accessible for a quantitative evaluation and finally for a medical diagnosis and therefore have to be brought out by appropriate statistical analysis.